Abstract

YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl) propyl]-2′-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) antagonizes leukotriene (LT) D₄ and thromboxane (TX) A₂ receptors. Functional assays in vitro showed that YM158 exhibits competitive dual antagonism of LTD₄ and TXA₂ receptor-mediated contraction of isolated guinea pig tracheae, with pA₂ values of about 8.87 and 8.81, respectively. Its antagonistic activity for the LTD₄ receptor was approximately 6.5 times less potent than that of montelukast, and that for the TXA₂ receptor was 2.5 times more potent than that of seratrodast. YM158 also inhibited PGD₂- and PGF_2α-induced tracheal contractions. YM158 showed no antagonism against LTC₄-, histamine- or carbachol-induced contractions of guinea pig tracheae. Furthermore, YM158 antagonized the stable TXA₂ analog U46619-induced aggregation of both guinea pig and human platelets and inhibited the LTD₄-induced contraction of guinea pig ileum. From these results, YM158 appears to be a novel, selective dual antagonist for both LTD₄ and TXA₂ receptors.